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    • 专利摘要:
    The invention concerns 3,4-dihydropyrimido [1,2-a]benzimidazole derivatives bearing one or more substituents at positions 6, 7, 8 or 9; processes for their preparation and manufacture; and pharmaceutical compositions thereof. The compounds inhibit the aggregation of blood-platelets and may be used in vivo, in the treatment or prophylaxis of thrombosis or occlusive vascular disease, or in vitro, in helping to stabilize preparations of blood platelets. Representative compounds of the invention are 7- and 8- acetyl-3,4-dihydropyrimido[1,2-a]benzimidazol-2(1H)-one.
    公开号:SU843751A3
    申请号:SU772552626
    申请日:1977-12-09
    公开日:1981-06-30
    发明作者:Деннет Миллз Стюарт
    申请人:Империал Кемикал Индас Триз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new azole benzimide derivatives with antiplatelet properties of platelets and which can be used in medicine. The known reaction of 2-aminoimidazole derivatives with ethylenecarboxylic acid derivatives with the formation of pyrimido- (1,2-a) -imidazole 1. The purpose of the invention is a method for producing new benzimidazole derivatives with valuable pharmacological properties. The goal is achieved based on a known reaction method for the preparation of benzimidazole derivatives of the general Formula 1. Г К „- are identical or different where RI are significant and are hydrogen. Or alkyl d. With 1-4 carbon atoms / one, two or three substituents from among A4, A, j, АТ, And А4 are the same or different and are halogen, hydroxy with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkythio group with 1-4 carbon atoms, alkanoyl with 2-4 carbon atoms, 1-oxyalkyl with 1-4 carbon atoms, cyano group, or benzoyl, perhaps substituted by halogen, or cyano, and the remaining substituents from A, Aa, A2, and A are hydrogens} or two adjacent substituents from among A (, Ac, A and A together form an alkylenedioxy group with 1-6 carbon atoms, the other substituents from among A (, Ay, A and. A / are hydrogen) provided that when only one of the substituents from Ajf, A, An and Aif is halogen, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms, then at least one of the remaining substituents from A, A, A and A has a value different from hydrogen The method consists in that 2-aminobenzimidazole of the general formula 11 A4 AZ-.A-1,
    where A (have the above values, is reacted with an ethylene carboxylic acid derivative of the formula fTi
    Eg-C31 SJ, -C02l (ft) where R, and R have the specified values, and 2 are halogen or alkoxy with 1-4 carbon atoms.
    In connection with the known tautomerism of the 3-, 4-dihydropyrimido- (1, .2-a) -benzimidazole-2- (1H) -one derivatives, the compounds according to the invention may exist in different tautomeric. The forms, which are also part of the invention, in order to simplify the nomenclature of the compounds according to the invention indicate one of the possible tautomeric forms.
    The method is preferably carried out at 15-80 ° C in an inert solvent or diluent under the reaction conditions, for example, in methanol, ethanol, acetone, tetrahydrofuran, acetonitrile.
    In the case when ill 2 is a halogen in the starting compound, it is advisable to use a hydrogen halide acceptor, such as a tertiary amine, such as triethylamine.
    Derivatives of pyrido (1,2-a) -benzimidazole formula T have the property of inhibiting platelet aggregation. This vitro activity is determined by adding a test compound to a stirred sample of platelet-rich and treated with human blood plasma citrate and determining the slowing down or reduction of platelet aggregation caused by the addition of collagen or adenosine-5-diphosphate. In this test, the compounds of Formula 1 significantly inhibit the aggregation platelets at concentrations of the order of mol per liter or less,
    For example, an equimble mixture of 7- and 8-acetyl-3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) -ones causes a significant inhibition of platelet aggregation even at a concentration of 10 mol / L.
    Platelets, if stored for several hours and then administered to animals or humans, tend to lose most of their hemostatic (hemostatic) activity. Compounds that inhibit platelet aggregation in vitro are for this reason very useful agents for stabilizing platelet-containing drugs. Therefore, these compounds can be used by adding them, for example, to whole blood in order to ensure its long-term storage in special blood banks / or to ensure the circulation of whole blood through isolated organs before their transplantation or through heart-lung blood circulation apparatus. - light It is just as useful to add such compounds to platelet suspensions prepared for use in the treatment of congenital or drug-induced thrombocytopenia.
    The ability of compounds of formula I to inhibit platelet aggregation in vivo is determined by standard tests on rats or mice that artificially cause thrombopenia. For example, a test compound is orally administered to rats, and then, after several hours, adenosine 5 -diphosphate (ADP) is administered intravenously at a dose of 5 mg / kg After 15 seconds, an arterial blood sample is taken from the experimental rats and using an electronic cell counter, platelet counts are made in this sample. The results of this calculation are then compared with the results of a similar determination of the number of platelets in the arterial blood sample, taken immediately before the administration of adenosine 5-diphosphate to rats. Administration of ADP causes noticeable thrombopenia, which reaches its maximum in approximately 15 seconds. Compounds that inhibit this thrombopenia induced by ADP administration are considered active.
    In another standard test, eight mice were administered an orally determined dose of the test compound. After 4 h thereafter, a solution of collagen (1 mg / kg) in an appropriate solvent was injected intravenously into four mice of another group, while the rest of the mice were injected in the same way with one solvent (control group of animals). After 1 min after injection, arterial blood samples were taken from all groups from all groups and counted in them by the standard method, the number of platelets. As in the previous test, compounds that inhibit thrombopenia induced by intravenous administration of collagen are considered active in this case. The in vivo biological activity of compounds of formula I varies depending on their chemical structure, but, in general, compounds of formula 1 exhibit activity in one or both of the above in vivo tests at doses of about 100 mg / kg or less, without causing any obvious toxic effect or other side effects. Thus, for example, an equimolar mixture of 7- and 8-cyano-3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (IH) -OHOB showed significant activity upon peroral administration in doses of 25 and 50 mg / kg.
    respectively, with ADP-induced .nol and collagen-induced thrombepenia without any signs of toxicity or other side effects.
    Compounds that inhibit platelet aggregation in vivo can be used to treat and prevent thrombosis or other diseases associated with blockage of blood vessels.
    The following examples illustrate the production of source and target products.
    Examples 1-3. To a solution of 27.2 g of 2-a 1ino-5, b-dimethylbenzimidazole in 100 ml of ethanol was added 15 g of methyl acrylate. After stirring for 2 days at room temperature, the crystalline precipitate is filtered off, washed with ethanol and then with diethyl ether, and after drying in vacuum (until constant weight), 37.2 g of 7.8 dimethyl-3,4-dihydropyrimide ( 1,2-a) -benzimidazol-2 (1H) -one, so pl. 322-323С.
    "
    Similarly, using the corresponding 2-aminobenzimidazole and methyl acrylate (MA), the pyrimido- (1,2-a) -ben zimidazole derivatives listed in Table 1 are obtained.
    The starting compounds of formula II are prepared as follows.
    2-AMINO-4,7-dimethylbenzimidazole (for example 2).
    A mixture of 70.0 gp-xylylenediamine (obtained by catalytic hydrogenation of a mixture of dinitro-p-xylenes, which is a product of nitration of p-xylene), which contains 3, b-Dimethyl-1,2-diaminobenzene, is converted into the corresponding monohydrochloride salt by adding 270 - ml 2 n. aqueous solution of hydrochloric acid and the subsequent evaporation of the resulting solution. A mixture of 86.2 g of monohydrochlorides of p-xylylenediamines in 120 ml of water is heated to boiling and a solution of 23.1 g is added to the boiling mixture. cyanamide in 50 ml of water. After refluxing for 1 hour, the reaction mixture is made alkaline by adding a solution of 20.8 g of sodium hydroxide in 50 ml of water. The resulting mixture is then boiled for an additional 18 hours and then cooled. The resulting oil is separated by decantation and then treated first with water (250 ml) and then chloroform (3 150 ml portions). The remaining dark gum is dissolved in 150 ml of acetone and the resulting solution is purified by fractional chromatography on a column of silica gel (1.5 kg) using as; eluent first methanol-chloroform (1: 1 p volume), and then pure methanol. Steaming the combined methanol fractions yields 13.9 g of 2-amino-4,7-dimethylbenzimidazole, which is then recrystallized from ethanol. In the end, get 6.1 g of pure substances with so pl. 1b4-170S.
    2-amino-5, b-diisopropoxybeneimidazole (for example 3).
    A solution of 2.24 g of 1,2-diamino-4,5-diisopropoxybenzene in 40 ml of methanol is added to 1.6 g of bromine cyan in
      40 ml of water. The reaction mixture was stirred at 20-25 ° C for 70 hours, and then tweaked by adding an excess of aqueous ammonia solution (d 0.88). After separation of the solid precipitate by filtration, the filtrate is evaporated to dryness. The residue obtained is taken up in 50 ml of water and 50 ml of chloroform. The chloroform phase is separated, dried with anhydrous magnesium sulphate and
    0 then evaporated. The gummy residue is purified by chromatography on a column of 40 g of silica gel using methanol-chloroform system (1: 3 by volume) as eluent.
    5 1.2 g of 2-amino-5,6-diisopropoxybenzimidazole.
    Examples 4 and 5. Using a procedure similar to that described in Example 1, and starting from 1.0 g of methyl acrylate and 1.75 g of 2-amino-5-chloro-6-methylbenzimidazole, 0.8 g of a mixture of 7-chloro-8-methyl-3 is obtained, 4-dihydropyrimido (1,2-a) -benzimidazol-2 (1H) -one (Example 4) and 8-chloro-7-methyl-3,4-dihydropyrimido- (1,2-a) -benzimidazole 5 -2 (1H) -one (Example 5) in a 1: 1 ratio. The resulting mixture has a melting point higher.
    The ratio of ingredients equal to 1: 1, is established by the method of PMR. In the aromatic proton region, for a solution of a substance in trifluoroacetic acid relative to tetramethylsilane (TMS), used as an internal standard, there are 4 signals with (I 7.72 (singlet), 7.59 (singlet), 7.47 (singlet) of the same integral intensity.
    The original 2-amino-5-chloro-6-methylbenzimidazole was obtained in the form of a solid with a yield of 1.74 and
    0 m.p. 240-247C. by the interaction of 2.43 g of bromine cyan with 2.4 g of 4-chloro-5-methyl-1, 2-diaminobenzene.
    Examples 6 and 7. Using a procedure similar to that described in Example 1, starting from 0.77 g of methyl acrylate and 1.45 g of 2-amino-5-methylthiobenzimidazole, 0.9 g of a mixture of 7-methylthio-3, 4-dihydro-pyrimido- (l , 2-a) -benzimidazol-2 (1H) -one (example 6} and 8-methylthio-3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) -one (example 7), equimolar ratio of the indicated compounds (1: 1). This mixture of isomers has a melting point of 2345: 238 C, and its NMR spectrum is
    in CD, COOD, shows 6 signals from aromatic protons at сI108.9, 107.9, 116.0, 114.6 and 132.3, 130.9 ppm relative to tetramethylsilane (TIS), used as an internal standard (signals have the same integrated intensity).
    The starting 2-amino-5-methylbenzimidazole is obtained as a solid with mp. 195-210 ° C, with a yield of 1.45, a reaction of 2 .06 g of bromine cyan and 2 g of 4-methylthio-1,2-diaminobenzene. The resulting compound was sufficiently pure for further use.
    Examples 8-11. To a solution of 26.0 g of 5-acetyl-2-aminobenzimidazole in 200 ml of ethanol was added 14.5 methyl acrylate. The resulting solution was heated under reflux for 20 hours, after which the reaction mixture was cooled. The crystalline precipitate formed is filtered off, washed with ethanol and diethyl ether and, after drying in vacuo to constant weight, 31.7 solids are obtained which are recrystallized from dimethyl formamide (DMF) to give 29.5 g of a mixture (composition 1: 1 ), 7- and. 8-acetyl-3, 4-dihydropyrimido- (1,2-a) -benzimidaz6l-2 (1H) -ones (example 8) This mixture has so pl. above and identified according to NMR spectroscopy.
    Elemental analysis.
    Calculated,%: C, 62.9; H 4.8; N 18.3.
    Found,%: C 62.8; H 4.7; N 18.4.
    The NMR spectrum of the product, taken in trifluoroacetic acid, shows two triplets, at 4.50 and 4.55, corresponding to a proton at C (equal integral intensity).
    Similarly, using the corresponding 2-amino-benzimidazole of the formula II and methyl acrylate, three other compounds of the formula I indicated in Table 2 are prepared.
    5-acetyl-2- (Eminobenzimidazole (for Example 9).
    A solution of 38.7 g of 4-amino-3-nitroacetophenone in 1 liter of ethyl acetate containing 10 mg of hydroquinone is hydrogenated in the presence of a palladium catalyst {10% palladium on activated carbon) at room temperature and atmospheric pressure until the absorption of hydrogen ceases. The catalyst is separated, filtered, and the filtrate is evaporated to dryness. The solid residue is stirred in 100 ml of water, then separated and, after drying to constant weight, 28.6 g of 3,4-diamino acetophenone are obtained with a mp of 131134 ° C.
    To a suspension of 25 g, L1-Diam (noacetophenone in 400 ml of motanol 1 is added with stirring 20 g of cyanogen bromide in 400 ml of water. The reaction solution is kept at room temperature for 16 hours and then evaporated. The residue is dissolved in water and alkalized by adding an excess of saturated sodium carbonate solution. The suspension is stirred for 1 hour, the solid is filtered off, washed with water and dried to constant weight. 26.6 g of 5-acetyl-2-aminobenzimidazole / m.p. -234 0.
    2-amino-5-cyanobenzimidazole (for 5 of Example 11).
    Using a procedure similar to that described above, starting from 7.8 g of 3,4-diaminobenzonitrile and 6.9 g of cyanogen bromide, 8.1 g of 2-amino-5-cyo-nobenzimidazole are obtained in the form of a solid with mp. 228-233 p. The purity of the product obtained is sufficient for further use without further purification.
    2-amino-5,6-methylenedioxybenzimideable (for Example 12).
    To a solution of 3.8 g of 3,4-methylenedioxy-0-phenylenediamine in 60 ml of ethanol, 3.4 g of bromine cyanide in 60 ml of water was added while peremegivanie. The reaction gives 4.4 g of 2-amino-5,6-methylenedioxybenzimidazole, m.p. 230-243 0.
    Example 12. An equimolar mixture (1: 1) of 7- and 8-ace1-l-3,4-dihydropyrimido- (1,2-a) -benzimidazole-2 (IH) -OHOB (1.5 g) is dissolved in 100 ml of boiling dimethylformamide and in the resulting solution are injected as a seed crystal of a pure sample
    8-acetyl-3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) -one. The solution was allowed to cool to room temperature and, after some time, the formation of two distinctly different crystalline forms — light crystals, enriched with 8-acetylisomar, and heavy crystals, which were enriched with 7-acetyl isomer — were observed (in each case, NMR - spectroscopy). These two crystalline forms separate the Y. by stirring the mixture up and then removing the light crystals together with the mother liquor by decanting. This method was able to obtain sample (A) with a weight of 0.05 g, containing 80% of the 7-acetyl isomer. The specified sample (L) is then used as a seed
    0 for crystallization from a solution of an equimolar mixture of 7- and 8-isomers (weighing 4.0 g) in 300. ml of boiling dimethylformamide. As a result of this procedure, a portion of light crystals (B) and heavy crystals (C1
    which are separated by decanting. The light crystals (B) thus obtained are heated with their mother liquor and a sample of the pure 8-acetyl isomer is introduced into the hot solution as a seed. In this case, an additional portion of light crystals (D) and heavy crystals (E) was obtained. The light crystals (D) are then re-dissolved in their matric fluid, and the pure 8-isomer is again inoculated into the resulting solution, as a result of which the formation of another portion of light crystals (F) and heavy crystals (G) is observed.
    Portions of heavy crystals C, E and G are combined and recrystallized twice (without seed crystals) from boiling dimethylformamide. As a result, 0.65 g of 7-acetyl-3, 4-dihydropyrimido (1,2-a) -benzimidazole-2 (1I) -one with mp. above .
    Elemental analysis.
    Calculated,%: C, 62.9; H 4.8; N 81.3.
    Found,%: C 62.4; H 4.8; N 17.9,
    NMR spectrum (in trifluoroacetic acid):
    f 2.81 (singlet, 3 protons, COCH.); 3.42 (triplet, 2 protons,

    d4,75 (triplet, 2 protons)
    7.84 (doublet, 1 proton, Cd-H).
    A similar recrystallization of the fraction of light crystals from boiling dimethylformamide results in a sample of 8-acetyl-3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H-one, having a melting point of 320 ° Cj NMR 2.55 (singlet, 3 protons,,); 3.0 (triplet of 2-proton, Cj-H /)), 4.42 (triplet of 2 protons, C4-H (); 7.64 (doublet, 1 proton, Cg; H), 7.95 (multiplet, 1 proton, Cf-H) and 8.05 (singlet, 1 proton, Cd-H).
    Elemental analysis.
    Calculated%: C 59.9; H 5.1; N 17.3.
    Found,%: C 59.3; H 4.7; N 17.0.
    Examples 13-16. Using a procedure similar to that described in Example 8, starting from the corresponding 2-aminobenzimidazoles and methyl acrylate, the following compounds of formula 1 are obtained with 70% to 90% with a strain of 70%.
    Example 13. An equimolar mixture (1: 1) of 7- and 8-butyryl-3,4 dihydropyrimido- (1,2-a) -benzimidaeol-2 (1H) -ones is obtained as a solid with mp. 287-300 0 (after recrystallization from dimethylformamide).
    Elemental analysis.
    Calculated,%; C 65.4; H 5.8; N 16.3.
    Found,%: C 65.0; H 5.9; N 16.2.
    An NMR spectrum (in trifluoroacetic acid) contains 2 identical triplets (SL-H,) in the range of d 4.66 and 4.70. The product is obtained by boiling 5-butyryl-2-aminobenzimidazole with methyl acrylate in ethanol for
    0 72 h.
    Example 14. An equimolar mixture (1: 1) of 7- and 8- (-chlorobenzoyl) -3, 4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) It is obtained in the form of a solid substance m. square 315-325c.
    five
    Calculated,%: C 62.7; H 3.7;
    N 12.9; C1 10.9 ..
    Found,%: C 62.2; H 3.5;
    N 12.4; C1 10.8.
    NMR spectrum (in trifluoroacetic
    0 acid): cf 3.30 (triplet, 2 protons Cn-H, j); 4.60 (triplet, 2 protons Cd-H,); 7.71 (singlet, 1 proton, Cg-H); 7.86 (singlet, 1 proton, Cd-H). The product is obtained by boiling
    5 5- (-chlorobenzoyl) -2-aminobenzimidazole with methyl acrylate in methanol for 16 h.
    Example 15. 7,8-dichloro-3,4-dihydropyrimido- (1,2-a) -ben 3imido 0 azole-2 (1H) -one is obtained in the form of a solid with mp; higher than 45c
    Calculated,%: C 46.9; H 2.7; N 16.4.
    Found,%; C, 46; H 2.8;
    5 N 16.4.
    The product is obtained from 5,6-dichloro-2-aminobenzimidazole and methyl acrylate in ethanol by boiling the reaction mixture under reflux for 72 hours.
    0
    PRI mme R 16. A mixture of 8.9 and 6,7-dimethyl-3,4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) -ones (in a molar ratio of 49: 1) get in the form of a solid substance with so pl, 2405 2440s (after recrystallization from ethanol).
    Calculated,%: C65,5; H6,2; i N 19.1.
    Found,%: C 65.5; H 6.2;
    0 N 19.0.
    The NMR spectrum (in trifluoroacetic acid) contains two triplets in the region of s4.42 (, from the 8.9 isomer) and 4.10 (Cd-Ny from the a, 7-isomer) with respect to 49il, respectively. This product is obtained by treating 4,5-dimethyl-2-.aminobenzimidazole with methyl acrylate in ethanol at room temperature.
    Q
    The required starting materials and the corresponding derivatives of 2-aminobenzimidazole with the general formula P were obtained according to the procedure described in example 8.
    Example 17. A mixture of 2.37 g of 2-amino-5-benzylbenzimidazole and 1.1 g of methyl methacrylate is refluxed in 20 ml of ethanol for 72 hours, after which another 0.8 g of methyl methacrylate is added and the reaction mixture is boiled t even over b days. Next, the mixture is cooled down to room temperature and the solid precipitated / separated by filtration, washed successively with ethanol and diethyl ether. A total of 1.4 g of an equimolar mixture (1: 1) of 7- and 8-benzoyl-3, 4-dihydro-3-methylpyrimido- (1,2-a} benzimidazole-2 (1N) -one with t is obtained. pl. 296321 p.
    Calculated,%: C, 70.8; H 4.9; N 13.8.
    Found,%: C 70.4; H 4.9; N 13.6.
    An NMR spectrum (in trifluoroacetic acid; it contains two doublets (C, j-H) in the region of C 4.84 and 4.93 of equal intensity.
    Example 18 A mixture of 2.4 g of 2-amino-5-benzoylbenzimidazole and 1.25 g of ethyl crotonate is boiled in 20 ml of 1-butanol for 4 days. After cooling the 4 reaction mixture, the resulting solid precipitate is separated by filtration and recrystallized from methanol to obtain 0.5 g of a solid product, which, according to NMR spectroscopy, is a mixture of 7- and 8g-benzoyl-3,4-dihydro-4-methylpyrimido- 1,2-a) -benzimidazole-2 (1H) -one composition of 2: 1. Evaporation of the mother liquor remaining after recrystallization of the said product from methanol yields 1.35 g of an equimolar mixture of (1; 1) 7- and 8-benzoyl-3, 4-dihydro-4-methylpyrimido- (1,2-a ) -benzimidazole-2 (1H) -ones with so pl. 250-2700С.
    Calculated,%: C, 70.8; H 4.9; N 13.8. ,
    Found,%: C 71.0; H 5.2; N 13.9.
    In the NMR spectrum there are two doublets (, h) in the region of 1.24 and 1.31 of equal intensity.
    P r and m, .19. Using a procedure similar to that described in Example 1, and starting from 2.8 g of methyl acrylate and 6.3 g of 2-amino-5-ethylthiobenzimidazole, 3.1 g of an equimolar mixture (1: 1) of 7- and 8-ethylthio- 3,4-dihydropyrimido- (1,2-a) -benzimidazol-2 (1H) -oiov with so pl. 185-186OS. In the NMR spectrum of the product, there are two triples of equal intensity (SL, -HL) in the G 4,22 and 4,23 region.
    The original compound was prepared as follows. 2.75 g of metallic sodium was added to 75 ml of dry 2-methoxyethanol and the resulting solution was cooled to 0-5 sec. To that.
    a solution of 8.72 g of ethanethiol in 10 ppm of 2-methoxyethanol was added to the solution with stirring for 5 minutes, then the reaction solution was stirred for 10 minutes, and then a solution of 21.5 g was added in portions of 5 with stirring -chloro-2-nitroacetanilide in 150 ml of boiling 2-methoxyethanol, and the addition is completed within 10 minutes. After 3 h thereafter, the reaction mixture is cooled and poured into a beaker containing 1 l of water. The resulting mixture is thoroughly mixed and cooled to. The resulting solid precipitate is filtered, washed with water and recrystallized from ethanol. In a mixture, 16.4 g of 5-ethylthio-2-nitroaniline are obtained with mp 755.7 C.
    A solution of 8/2 g of 5-methylthio-2-nitro0 aniline in 100 ml of ethanol is hydrogenated in the presence of 0.8 g of 10% palladium on activated carbon. 75 ml of water are added to the reaction mixture under a nitrogen atmosphere and then a portion of mi for 10 min 8.7 g bromine cyan. After stirring for 3 days at room temperature, the reaction mixture is filtered and the filtrate is concentrated in vacuo to a small volume. 75 ml is added to the residue first.
    0 water and then a 10% solution of sodium carbonate in order to bring it to a pH of 8. The solid precipitate thus formed is filtered off, washed with water, air dried and after
    5 treatment with acetone receive 6,3 2-amino-5-ethylthiobenzimidazole.
    Example 20. A mixture of 2.6 g of 2-amino-6,8-dimethylbenzimidazole and 0 1.5 g of methyl acrylate is stirred in 25 ml of ethanol for 5 days. The solid precipitate thus formed is filtered and washed successively with ethanol / 5 acetone and diethyl ether. A total of 2.1 g of a mixture (9: 1) of 7.9 and 6.8-dimethyl-3,4-dihydro-pyrimido - (1, 2-a) -benzimidazole-2 (1H) -ones as a solid product with t .p.3260 3320s
    Calculated,%: C 67.0; n 6.0;
    N 19.5. Found,%: C 66.7; H 6/1;
    N 19.5.
    f The NMR spectrum shows two triplets (C / i-H,) in the region (f 4.01 (7,9-isomer) and 4/32 (6,8-isomer) in a ratio of 9: 1, respectively.
    Example 2: To a solution of 12.2 g of 2-amino-5, b-dimethoxybenzimidazole 0 in 70 ml of methanol was added 6/1 g of methyl acrylate and the reaction mixture was stirred for 90 hours. The crystalline precipitate was filtered off , washed successively with eta5 -NOL and diethyl ether and dried in
    vacuum to constant weight. A total of 10.3 g of 7,8-dimethoxy-3/4-dihydropyrimido- (1,2-a) -benzimidazole-2 (1H) -one with m.p. 264-2b5 with. .
    Calculated,%: C 58.3; H 5.3; N 17.0.
    Found,%: C 58.0; H 5.2; N 16.8.
    NMR spectrum: (I 2.82 (triplet, 2 protons, C, o, -H (); 3.72 (singlet, 3 protons, CHijO); 3/76 (singlet, 3 protons, СНо, О); 4 , 15 (triplet, protons Ci, Hii); 7.00 (singlet, 1 proton); 7.04 (singlet, 1 proton, C – H).
    Example 22. A mixture, 3 g of 2-amino-6 .3-dimethylbeneimidazole and
    5.3 g of methyl acrylate in 70 ml of methanol is refluxed for 1 hour under reflux. The crystalline precipitate thus formed is filtered directly from the hot solution and washed with methanol.
    In total, 2.4 g of a mixture of 7.9 and 6.8-dimethyl-3, 4-di1-i-pyropyrimido- are obtained. - (1,2-a) -benzimidazole-2 (1i) -ones, having so pl. 325-327c and containing 98% of the 7.9-isomer. Data on the composition of the mixture is obtained by using NMR spectroscopy of the product by comparing the triplets of the C / 4 -HU group in the range of 4.01 (7.9-isomer) and 4.32 (6.8-isomer).
    L b l and c a 1
    ) T ope
    Note: A,
    Note: V.
    The reaction mixture was boiled for 2 days under an inert gas atmosphere, using a mixture of ethanol (10 ml) and methanol (2 ml) as a solvent.
     T a b .p and I a 2
    The product is isolated as an equimolar mixture of 7- and 8-benzoyl-3,4-dihydropyrimido (1,2-a) -beysimidazole-2- (1H) -ones; PMR spectrum of the product :, СЯ2.90 (triplet, 2 protons,); 4.30 (triplet, 2 protons,,); 7.4-7.8 signal from 8 aromatic protons.
    The product is an equimolar mixture of (1: 1) - 7- and 8-cyano-3, 4-dihydropyrimido- (1,2-a) -benzimidazole-2 (1H) -okov, according to NMR spectroscopy (the presence of two equal singlets with cC7.9.8 Cd-H 8-CN isomer) and cC7.89 (Cj, -H, 7-CN isomer).
    权利要求:
    Claims (2)
    [1]
    Claim
    1. A method of producing benzimidazole derivatives of the general formula 1 wherein R 1 and R ^ are the same or different and are hydrogen or alkyl with 1-4 carbon atoms; one, two or three substituents from among A 4 , Α; χ, A ^ and Ad are the same or different and are halogen, alkyl with
    1-4 carbon atoms, alkio group with 40 1-4 carbon atoms, alkanoyl with 2-4 carbon atoms, 1-hydroxy alkyl with
    1-4 carbon atoms, cyano, benzoyl, optionally substituted by halogen or cyano, and the remaining 45 za- mestiteli number of A # t A , A3 and A4 are hydrogen; · or two adjacent substituents among A, A r, A ^ and Ad together form an alkylenedioxy group with 1-6 atdma of carbon, the other jq substituents from among A #, A th , A ^ and Ad are hydrogens, provided that when only one of the substituents from A | |, Αζμ A b and Az, is halo gene, alkyl with 1-4 carbon atoms or alkoxyl with 1-4 carbon atoms, then at least one of the remaining substituents of the number A ,, Α ^, Α ^ and A ^ has a value different from hydrogen, characterized in that 2-aminobenzimidazole of the general formula P where A, -Ad have the above meanings, are reacted with an ethylene carboxylic acid derivative of the formula III
    K 2- CH "SK1-S02, (w)
    I. .
    where R ( and R 2 have the above meanings, and Z is halogen or alkoxyl with 1-4 carbon atoms.
    [2]
    2. The method according to claim 1, characterized in that the process is carried out at 15-80 ° C in an inert solvent or diluent under the reaction conditions.
    Convention priority of 09.12.
    76 installed on the basis of
    R 1 and R 2 are all values, one or two or three of the numbers A ( , A 5 , A ^ and Ad are the same or different from the number of halogen, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, alkthio group with 1-4 carbon atoms or a cyano group, or two adjacent substituents from among A #, A 2 , A ^ and
    Hell together form an alkylenedioxy group with 1-6 carbon atoms, and other substituents from among A ^ ·, A a , A ^ and Ad are hydrogen; Z is halogen or alkoxy with 1-4 carbon atoms.
    Priority from 09.08.77 is established by:
    R ( and Rj are all values, one of A f , Α ^, Αα, and Ad is alkanoyl with 2-4 carbon atoms, 1- (hydroxy) alkyl with 1-4 carbon atoms or benzoyl substituted by halogen, the rest of A ( -Ad hydrogens.
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    同族专利:
    公开号 | 公开日
    ATA883677A|1980-03-15|
    PL107142B1|1980-01-31|
    US4167569A|1979-09-11|
    SE7713958L|1978-06-10|
    FR2373543B1|1980-05-16|
    ES464862A1|1979-01-01|
    FR2373543A1|1978-07-07|
    DE2754930A1|1978-06-15|
    IE45924B1|1982-12-29|
    HU176540B|1981-03-28|
    SE435385B|1984-09-24|
    FI773724A|1978-06-10|
    CH633291A5|1982-11-30|
    DD133330A5|1978-12-27|
    CS199696B2|1980-07-31|
    AT359068B|1980-10-27|
    IL53507A|1981-07-31|
    CA1086727A|1980-09-30|
    IL53507D0|1978-03-10|
    GR65298B|1980-08-01|
    JPS5390296A|1978-08-08|
    NL7713658A|1978-06-13|
    FI63577C|1983-07-11|
    FI63577B|1983-03-31|
    AU3112177A|1979-06-07|
    IT1143729B|1986-10-22|
    AU514427B2|1981-02-12|
    NZ185823A|1980-08-26|
    PL202753A1|1978-10-09|
    NO774216L|1978-06-12|
    IE45924L|1978-06-09|
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    US3988340A|1975-01-23|1976-10-26|Bristol-Myers Company|6-Alkoxymethyl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-ones and 7-alkoxymethyl-6-[H]-1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-2-ones|
    US4072679A|1976-06-15|1978-02-07|E. R. Squibb & Sons, Inc.|1,4- AND 4,10-DIHYDRO-4-OXO-PYRIMIDO -benzimidazole-3-carboxylic acids, esters and amides|CA1157858A|1979-12-03|1983-11-29|Ikuo Ueda|Quinazoline derivatives|
    IE51802B1|1979-12-03|1987-04-01|Fujisawa Pharmaceutical Co|Quinazoline derivatives,processes for their preparation and pharmaceutical compositions containing them|
    DE3208218A1|1982-03-06|1983-09-08|Basf Ag, 6700 Ludwigshafen|ISOINDOLINE DYES AND THEIR USE|
    UA116541C2|2012-06-27|2018-04-10|4Ск Діскавері Гмбх|Bifluorodioxalane-amino-benzimidazole kinase inhibitors for the treatment of cancer, autoimmuneinflammation and cns disorders|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB51426/76A|GB1585965A|1976-12-09|1976-12-09|3,4-dihydropyrimido benzimidazol - 2 - ones|
    GB3334177|1977-08-09|
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